Sepsis and multiple organ dysfunction syndrome (MODS) remain the leading cause of mortality in critically ill surgical patients, but specific effective therapies to counteract or ameliorate severe sepsis remain elusive. There is substantial evidence that macrophage and monocyte function is dysregulated in sepsis. In clinical sepsis and MODS patients are exposed to multiple inflammatory insults overtime. Profound modifications in LPS-stimulated macrophage function are seen when these cells have previously been exposed to LPS. The phenotypic alteration that results from prior exposure to inflammatory stimuli has been referred to as LPS-tolerance. In vitro LPS-tolerance is characterized by: diminished TNF and IL-6 secretion, impaired activation of ERK1.2, p38 kinase, IRAK, and altered regulation of nuclear factor kappa-B (NF-kappaB). Our overall goal is to better understand the mechanisms of dysregulated macrophage function during sepsis and we hypothesize that a "LPS-tolerant phenotype" is characteristic of sepsis and MODS. We propose 3 interrelated Specific Aims: Aim I: Compare and contrast the phenotypic "LPS-tolerant" states induced by bacterial ligands. Aim II: Identify and explore the feasibility of pharmacologically preventing or reversing LPS-tolerant states in vitro. Aim III: Determine whether patients (adults and children) with trauma, sepsis, or burns manifest the phenotypic alterations seen with in vitro LPS-tolerance. These efforts could ultimately lead to the development of new diagnostic tests to detect sepsis and suggest new treatments or better use of existing therapies to care for surgical patients with sepsis and MODS.